The Role of TRPM7 in Oncogenesis

This review summarizes the current understanding of the role of transient receptor potential melastatin-subfamily member 7 (TRPM7) channels in the pathophysiology of neoplastic diseases. The TRPM family represents the largest and most diverse group in the TRP superfamily. Its subtypes are expressed in virtually all human organs playing a central role in (patho)physiological events. The TRPM7 protein (along with TRPM2 and TRPM6) is unique in that it has kinase activity in addition to the channel function. Numerous studies demonstrate the role of TRPM7 chanzyme in tumorigenesis and in other tumor hallmarks such as proliferation, migration, invasion and metastasis. Here we provide an up-to-date overview about the possible role of TRMP7 in a broad range of malignancies such as tumors of the nervous system, head and neck cancers, malignant neoplasms of the upper gastrointestinal tract, colorectal carcinoma, lung cancer, neoplasms of the urinary system, breast cancer, malignant tumors of the female reproductive organs, prostate cancer and other neoplastic pathologies. Experimental data show that the increased expression and/or function of TRPM7 are observed in most malignant tumor types. Thus, TRPM7 chanzyme may be a promising target in tumor therapy.


TRP Channels
The transient receptor potential (TRP) superfamily consists of non-selective cationpermeable channels, of which 28 polymodal ion channels have already been identified in mammals [1][2][3][4].The TRP superfamily can be divided into seven subgroups based on sequence homology and membrane topology: the TRP-canonical (TRPC), TRP-vanilloid (TRPV), TRP-melastatin (TRPM), TRP-polycystin (TRPP) TRP-Mukolipin (TRPML), TRP-Ankyrin (TRPA) and TRP-NOMPC (TRPN; "N" stands for no mechanoreceptor potential C) ion channel subfamilies [4][5][6].In general, TRP proteins function as ion channels in the plasma membrane, play a key role in cellular ion homeostasis, and often have a sensory function as well.TRP channels are expressed in all human organs and appear to play a central role in the pathophysiological processes of many diseases including carcinogenesis.An increasing amount of evidence indicates the connection between the various hallmarks of cancer and the altered expression/activity of multiple TRP channels [4,[7][8][9][10][11][12][13][14][15][16].TRP channels are composed of four subunits in a homomeric or hetero-oligomeric formation to create cation-selective channels [5,6,17].Each TRP ion channel subunit has a transmembrane domain (TMD), consisting of six segments (S1-S6) with a pore-forming loop (P-loop) between S5 and S6 [4,18].The intracellularly localized carboxyl and amino termini vary widely in amino acid sequence and length and contain domains and motifs that have a role in channel assembly, activation and functional regulation through protein-protein and protein-ligand interactions [18].Members of the TRP superfamily are Na + -and K + -permeable, and some are also permeable to divalent cations, such as Ca 2+ and Mg 2+ .TRP ion channels play 2. The TRPM7 Chanzyme TRPM7 (ChaK1, TRP-PLIK, and LTRPC7) protein is ubiquitously expressed in the human body.This protein is known to act as a chanzyme, since it has dual activity in its functional tertrameric composition.It is an ion channel allowing the flux of divalent cations (Ca 2+ , Mg 2+ , Zn 2+ , Mn 2+ , and Co 2+ ); on the other hand, it acts as a serine-threonine protein kinase (α-kinase) [2,17,32,33].Structurally, TRPM7 shares common features with other members of the TRPM subfamily: it has a TMD composed of six transmembrane helixes and the P-loop, an intracellularly localized N-terminal sequence that includes the TRPM homology region and a large cytosolic C-terminus that contains the TRP helix, the coiled-coil domain [25,33,34] (Figure 1).The presence of a C-terminal α-kinase domain in TRPM7 (similar to its closest homolog, TRPM6) endows the protein with kinase activity as well.Due to the dual function of the protein, it is also called the "TRPM7 chanzyme".TRPM7 can phosphorylate serine/threonine residues of intracellular targets, including annexin 1 [35], myosin IIA, IIB, and IIC [36], histone H3 [37], RhoA [38] or Smad2 [39].

Role of TRPM Channels in Cancer
An increasing amount of evidence indicates the role of various TRPM proteins in pathophysiological processes related to carcinogenesis and cancer progression (Figure 2).Several studies demonstrate changes in mRNA and/or protein expression profiles for different TRPM channels in the various cancer types.Furthermore, data show that manipulations of TRPM channel expression and/or activity either via protein knockdown (silencing small interfering RNA, siRNA; short hairpin RNA, shRNA) [52,53] or using TRPM channel inhibitors [54,55] can significantly modify several hallmarks of cancer in the different tumor types [24,27,30,[56][57][58][59][60].For instance, in case of breast cancer, the expression of the TRPM2 channel is higher in both invasive and non-invasive tumors than in normal tissues.It has been also shown that TRPM2 has a protective role in breast cancer cells as it facilitates the integrity of genomic DNA by helping to minimize DNA damage.Nevertheless, TRPM2 promotes tumor growth in these cells [61][62][63].The TRPM8 channel also influences breast cancer hallmarks.It is overexpressed in breast adenocarcinoma cells correlating particularly with estrogen receptor-positive tumors [52,64,65].TRPM8 seems to be directly involved in invasiveness and metastasis by regulating epithelial-mesenchymal transition (EMT) [65,66].Furthermore, increased TRPM7 expression appears to play a key role in various characteristics of breast cancer cells, e.g., increased proliferation, altered cell adhesion, migration and invasion potential [27,67,68].
of the TRPM2 channel is higher in both invasive and non-invasive tumors than in normal tissues.It has been also shown that TRPM2 has a protective role in breast cancer cells as it facilitates the integrity of genomic DNA by helping to minimize DNA damage.Nevertheless, TRPM2 promotes tumor growth in these cells [61][62][63].The TRPM8 channel also influences breast cancer hallmarks.It is overexpressed in breast adenocarcinoma cells correlating particularly with estrogen receptor-positive tumors [52,64,65].TRPM8 seems to be directly involved in invasiveness and metastasis by regulating epithelial-mesenchymal transition (EMT) [65,66].Furthermore, increased TRPM7 expression appears to play a key role in various characteristics of breast cancer cells, e.g., increased proliferation, altered cell adhesion, migration and invasion potential [27,67,68].

Role of TRPM7 Chanzyme in the Pathophysiology of Various Tumors
Subsequent to the introduction of TRPM-related tumorigenesis, the following chapter focuses on TRPM7.

Glioblastoma
Numerous studies demonstrated the role of TRPM channels, including TRPM7, in the tumorigenesis of glioblastomas.The data have been summarized in excellent recent reviews [50,83].Functional expression of TRPM7 channels in human glioblastoma cells has been reported by several groups.The subsequently increased proliferation, migration and invasion of tumor cells were abolished via the knockdown or pharmacological inhibition of TRPM7 in various rodent and human glioblastoma cell lines.the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and extracellular signalregulated kinase kinase (MEK)/mitogen-activated protein (MAP) kinase signaling has been implicated in the observed effects [84][85][86][87][88][89][90][91][92].Liu et al. have demonstrated that TRPM7 activates Janus kinase 2/signal transducer and the activator of transcription 3 (JAK2/STAT3) and/or Notch signaling pathways, resulting in the activation of aldehyde dehydrogenase 1 (ALDH1) promoters and increased proliferation, migration and invasion in a human glioblastoma cell line [93].More recently, a detailed analysis has revealed that in TRPM7mediated Notch1 signaling, the expression of CD133 and ALDH1 are crucial in glioma cell proliferation and glioma stem cell stemness.Unlocking G1/S arrests, the stimulation of cell entry into S and G2/M phases and inhibition of glioma cell apoptosis are also important factors in the sequence of events [94].Wan et al. have proposed that the TRPM7 channel function was required for cell growth and proliferation while kinase activity was involved in increased migration and invasion.Furthermore, TRPM7 was shown to be a negative regulator of the tumor suppressor microRNA (miR)-28-5p [95].A recent publication has revealed that the TRPM7/HOX transcript antisense intergenic RNA axis is overexpressed in glioma cells promoting cell proliferation and invasion.These oncogenic effects have been (at least in part) mediated by the downregulation of miR-301a-3p (an inhibitor of glioma cell growth and invasion) resulting in a high expression of the oncogene FOS Like 1, which contributes to glioblastoma growth, progression and poor prognosis [96].
A Turkish survey found a significantly higher expression of several TRP channels including TRPM7 in glioblastoma patients [97].Notably, Tian et al. have reported that the pro-inflammatory prostaglandin E2, known to be elevated in glioblastoma, increases TRPM7 expression and responses as well as enhancing the migration and proliferation of tumor cells in human glioblastoma cells [98].Moreover, TRPM7 in glioblastoma cells has been reported to promote the vesicular transfer of chloride intracellular channel 1 (CLIC1) from glioblastoma to endothelial cells.CLIC1 has been proposed to modulate the activity of neighboring endothelial cells promoting angiogenesis [99] (Table 1).In a human neuroblastoma cell line, the MYCN oncogene has been reported to increase TRPM7 expression and thereby tumor cell proliferation and migration [100,101].Interestingly, the inhibition of both TRPM7 channel and TRPM7 kinase activity by fingolimod, a diseasemodifying immunmodulatory drug for the treatment of multiple sclerosis, has been observed in a human neuroblastoma MYCN-2 cell line.The concomitant changes in calcium signaling, loss of mitochondrial membrane potential and induction of apoptosis and autophagy may have clinical relevance, e.g., the sensitization of neuroblastoma cells to chemotherapeutic drugs.The possible repurposing of fingolimod for neuroblastoma was suggested [102].
In mouse neuroblastoma cells, TRPM7 was enriched at invadosomes (mechanosensory modules involved in cell adhesion and migration), and TRPM7 activity has been reported to regulate invadosome dynamics by affecting the tension-relaxation balance of the actomyosin cytoskeleton.This adhesion modulatory effect is supposed to be independent of Ca 2+ influx through the channel [103][104][105].A subsequent study revealed that TRPM7 enhanced metastatic potential, but not the proliferation rate in mouse neuroblastoma cells.TRPM7 overexpression conferred a malignant phenotype onto a poorly metastatic cell type in vivo.By maintaining progenitor-like features and controlling a developmental transcriptional program involving the transcription factor Snail family transcriptional repressor 2 (SNAI2), TRMP7 has been proposed to contribute to neuroblastoma progression [106].TRPM7, as a part of a cytoskeletal complex, has been suggested to be involved in the control of dynamic formation and the function of cell adhesions and cellular protrusions in mouse neuroblastoma cell line.Components of this TRPM7 interactome correlated with human neuroblastoma metastasis and disease outcome [107].Table 2 summarizes the role of the TRPM7 chanzyme in the pathophysiology of neuroblastoma as well as exemplifying the proliferative role of TRPM7 in retinoblastoma, another primitive childhood ectodermal tumor.4.2.Head and Neck Cancers 4.2.1.Nasopharyngeal Carcinoma A higher expression of TRPM7 proteins was found in a human nasopharyngeal carcinoma cell line exhibiting metastatic ability compared to cells without metastatic potential.The overexpression of TRPM7 enhanced Ca 2+ influx, which was critical for cell migration [109].Studies on tissue samples derived from patients with nasopharyngeal carcinoma showed that TRPM7 overexpression correlated with tumor metastasis and predicted poor prognosis (worse survival).TRPM7 has been proposed to be critical in the migratory and invasive activity of tumor cells and metastasis.The downregulation of TRPM7 reduced the invasiveness and motility of the tumor cells [110].Tumor proliferation regulated by TRPM7 was accompanied by the persistent activation of the JAK2/STAT3 signaling pathway.Moreover, the low expression of TRPM7 correlated with the better survival of patients with nasopharyngeal carcinoma.Remarkably, TRPM7 knockdown enhanced the sensitivity to irradiation [111].

Laryngeal and Hypopharingeal Carcinomas
Functional expression of TRPM7 channels has been demonstrated in a human hypopharingeal squamous cell carcinoma cell line.The activation of these channels was critical for the growth and proliferation of these tumor cells [112].The upregulation of TRPM7 by circular RNAs has been reported to enhance laryngeal squamous cell carcinoma progression [113].A recent study has confirmed the high expression of TRPM7 in head and neck squamous carcinoma cells, especially in invasive cancer tissues.Importantly, TRPM7 expression correlated with worse survival.Overexpression was demonstrated in cisplatin-resistant cases compared with cisplatin-sensitive subjects.The silencing of TRPM7 suppressed several oncogenic signaling axes and reduced the migration, invasion, colony formation and tumorsphere formation of human squamous cell carcinoma cells in culture [114] (Table 3).TRPM7 protein expression was only detected in esophageal squamous cell carcinoma cells but not in non-cancerous epithelia.However, surprisingly, TRPM7 was suggested to reduce the cell proliferation, migration and invasion of tumor cells [115].

Gastric Cancer
The role of the TRPM7 channel in the pathophysiology of gastric cancer has been repeatedly demonstrated.Human gastric adenocarcinoma cells have been shown to express TRPM7 channels that are possibly involved in the growth and survival of tumor cells [55,[116][117][118][119].A ginsenoside and some plant extracts from Korea and China have been reported to induce apoptosis, inhibit cell growth and survival by blocking TRPM7 proteins in human gastric adenocarcinoma cells [120][121][122].5-lipoxygenase inhibitors, waixenicin A and quercetin have been also demonstrated to decrease the TRPM7 channel function and cause the death of gastric cancer cells [123,124].A recent study has revealed that high TRPM7 expression is closely related to aggressive tumor behavior and an advanced stage, and was an indicator of poor prognosis in human gastric cancer [125] (Table 4).

Pancreatic Cancer
The overexpression of TRPM7 has been repeatedly demonstrated in human pancreatic adenocarcinoma, enhancing cell proliferation, migration and invasion [76,[127][128][129].Aberrant TRPM7-mediated signaling via the Mg 2+ -sensitive Socs3a pathway was implicated in the uncontrolled proliferation of neoplastic cells and pancreatic carcinogenesis [127].TRPM7 channels are expressed in pancreatic stellate cells involved in the development and progression of pancreatic ductal adenocarcinoma.The activation status of these cells seems to be correlated with TRPM7 expression.Furthermore, the overexpression of TRPM7 was also observed in cancer-associated fibroblasts [130].A recent study revealed that TRPM7 regulates pancreatic stellate cell proliferation through the modulation of cell cycle regulators.TRPM7 silencing or pharmacological blockade resulted in the accumulation of cells in the G0/G1 phase (accompanied by an increase in p53 expression and reduced cyclin E, cyclin-dependent kinase 2 and proliferating cell nuclear antigen expression), and abolished cell growth as well as decreasing cell viability [130].Moreover, the silencing of TRPM7 also enhanced the cytotoxic effect of gemcitabine [131].
TRPM7 has been suggested to increase cell migration through a Mg 2+ -dependent mechanism in human pancreatic cancer cells.TRPM7 expression correlated positively to a poorly differentiated status and reduced patient survival in pancreatic ductal adenocarcinoma [76].Lefebvre et al. have reported that elastin-derived peptides known to stimulate cancer cell migration by interacting with their receptor, ribosomal protein SA (RPSA), stimulated TRPM7 currents in pancreatic cancer cells in culture.Furthermore, TRPM7 and RPSA co-localized at the plasma membrane in human pancreatic cancer cells, and this complex was proposed to regulate cell migration [132].The control of the Hsp90α/urokinase/matrix metalloproteinase (MMP)-2 proteolytic axis was proposed as an underlying mechanism in the TRPM7-induced potentiation of pancreatic cancer cell invasion.Mg 2+ -entry through TRPM7 channels correlated with cell invasion and MMP secretion [77].

Liver Cancer
An inverse relationship was observed between the TRPM7 channel activity and differentiation status of rat embryonic hepatocytes.Higher TRPM7 protein expression has been reported in proliferating rat hepatocytes compared with that in differentiated and noninvading cells in culture [133].More recently, bradykinin has been demonstrated to promote the migration and invasion of human hepatocellular carcinoma cells by upregulating the expression of TRPM7 and facilitating the secretion of matrix metalloproteinase 2 (MMP2).The concomitant phosphorylation of non-muscle myosin heavy chain IIa and activation of calpains have been implicated in the relaxation of the actomyosin cytoskeleton and the turnover of peripheral adhesion complexes [134].A pharmacological blockade of TRMP7 resulted in the oncogene-induced senescence of human hepatocellular carcinoma cells in vitro and in vivo.Importantly, it has been reported that TRPM7 proteins regulate RhoA activity, actin polymerization, subsequent Myocardin-related transcription factor A (MTRF-A)-Filamin A complex formation and MTRF-A/Serum Response Factor target gene expression.Both Mg 2+ influx through the TRPM channel and the phosphorylation of RhoA by TRPM7 kinase have been suggested to be involved in the observed effect [38] (Table 5).

Colorectal Carcinoma
TRPM7 expression has been demonstrated in a colon cancer LoVo cell line.Remarkably, expression was lower in cells resistant to doxorubicin compared with doxorubicin-sensitive tumor cells, and TRPM7 was proposed to be involved in modulating drug resistance.High extracellular Mg 2+ and consequently increased intracellular Mg 2+ was suggested to downregulate TRPM7 through the activation of calpains in resistant cells.Lower TRPM7 expression also explained the slower proliferation of resistant cells [135,136].Huang et al. have reported that TRPM7 drives human colon cancer cell proliferation, and this effect was independent of systemic Mg 2+ status [137].TRPM7 expression was higher in human colon tumor samples compared with that in non-neoplastic tissue, and adenocarcinomas showed a higher TRPM7 expression than did adenomas.Moreover, TRPM7 expression positively correlated with tumor grade [138].An analysis of a public genomic database and patient data from a Chinese medical center revealed that expression of TRPM7 positively correlated with tumor infiltration, lymph node metastasis, distant metastasis and the clinical stage of colorectal cancer.The suppression of TRPM7 function reduced the cell proliferation, migration and invasion of colorectal cancer cells in vitro, by modulating EMT [139].A recent analysis of public data revealed that TRPM7 expression was higher in younger patients with rectal cancer, and TRPM7 expression positively correlated with APC and KRAS gene expression, while it was inversely related to p53 expression in rectal cancer.Nevertheless, survival analysis showed that TRPM7 expression did not have any prognostic value in colon and rectal cancers [140].
The calcium/magnesium intake ratio and their balance regulated by parathyroid hormone and TRPM7 have been implicated in the development of colorectal carcinoma [141,142].Furthermore, magnesium deficiency with physiological Ca 2+ concentrations (i.e., increased Ca 2+ /Mg 2+ ratio) was associated with increased TRPM7 expression, oxidative stress, induced calpain activity, increased cell migration and a more aggressive, metastatic phenotype of colon cancer cells [143] (Table 6).

Lung Cancer
The functional expression of TRPM7 receptors was demonstrated in a human nonsmall cell lung cancer cell line.EGF was shown to increase TRPM7 expression and function, and TRPM7 was suggested to be critically involved in the EGF-induced migration of tumor cells [144].Correspondingly, TRPM7 was aberrantly expressed in human lung cancer tissue samples and various cell lines and was found to be an independent indicator of poor prognosis in lung cancer.Increased TRPM7 expression was associated with enhanced cancer stem-like and metastatic phenotypes.TRPM7 enhanced the Hsp90α/urokinasetype plasminogen activator (uPA)/MMP2 signaling pathway.TRPM7 silencing inhibited epithelial-to-mesenchymal transition, and suppressed stemness markers and phenotypes.Waixenicin A, a TRPM7 inhibitor, also suppressed the cancer stem cell phenotype of lung cancer cells [145].More recently, the TRPM7/O-linked-β-N-acetyl glucosaminylation (O-GlcNAcylation) axis was suggested to represent a novel target for lung cancer therapy.Non-small cell lung cancer cell motility was shown to be modulated by TRPM7 and Ca 2+influx through O-GlcNAcylation.The hyper-O-GlcNAcylation of Caveolin-1 (Cav-1) and c-Myc resulted in increased tumor cell motility, and enhanced cell migration and invasion.Increased TRPM7 expression correlated with a reduced survival rate of tumor patients and more aggressive tumor phenotype.The inhibition of TRPM7 decreased cell motility and suppressed experimental lung metastases [146] (please see the summary of these data in Table 7).

Neoplasms of the Urinary System 4.6.1. Kidney Cancer
An overexpression of TRPM7 in human renal cell carcinoma cell lines and tissues has been reported.It was associated with the increased proliferation and colony formation of tumor cells in vitro and tumor growth in vivo, in line with an aggressive phenotype and poor survival.TRPM7 has been shown to promote Akt phosphorylation, resulting in the repression of the tumor suppressor Forkhead box-O1 (FOXO1)'s transcriptional activity [147].A prominent role of TRPM7 channels in the migration and invasion of human renal cell carcinoma cells via the Akt and Src pathways has been also suggested.The downregulation of TRPM7 prevented the migration and invasion of tumor cells [148] (Table 7).

Bladder Cancer
Increased TRPM7 expression was observed in mouse MBT-2 bladder tumor cells compared with that in normal mouse urothelial cells [149].TRPM7 was also overexpressed in human bladder cancer tissue and this increased expression was associated with tumor recurrence, metastasis and poor prognosis.TRPM7 knockdown by siRNA revealed that TRPM7 promoted bladder cancer cell proliferation, migration and invasion [150,151].Cao et al. have reported increased TRPM7 expression and the dysregulation of proteins involved in EMT in human bladder cancer tissues and cancer cell lines.The downregulation of TRPM7 reversed the EMT status, inhibited the proliferation, migration and invasion of cancer cells, and promoted cell cycle arrest at the G0/G1 phase and apoptosis [152].TRPM7 has been reported to regulate tumor growth, migration and invasion via the Src, Akt and c-Jun N-terminal kinase (JNK) signaling pathway in human bladder cancer cell lines [153].In line with these data, oridonin, an anticancer compound, exhibited antiproliferative and antimigratory effects and induced apoptosis by suppressing TRPM7 expression and extracellular signal-regulated kinase (Erk) and Akt signaling in human bladder cancer cells in culture [154] (Table 7).

Breast Cancer
The oncogenic roles and therapeutic potentials of TRPM7 in breast cancer are intensely investigated.More details are available in a recent comprehensive review [49].
The functional expression of TRPM7 and thre regulation of tumor cell proliferation by this channel have been reported in human breast cancer cells.TRPM7 was overexpressed in grade III tumors, and its expression positively correlated with the mitosis marker Ki67 [155].Subsequently, a high expression of TRPM7 in human breast cancer cells and tissue, as well as its correlation with proliferation, has been repeatedly demonstrated [67,[156][157][158].Remarkably, in a Chinese population, an association between the single-nucleotide polymorphism of the TRPM7 gene and breast cancer has been observed [159].Epigenetic alterations of TRPM7 are supposed to influence the clinical outcome of breast tumors.A recent study has demonstrated that TRPM7 was highly expressed in the luminal A subtype of breast cancer.Nevertheless, the promoter methylation of TRMP7 was associated with a better prognosis of the disease [160].
Interestingly, increased TRPM7 expression was found in human infiltrating ductal breast carcinoma samples with microcalcifications compared with that in tumors without calcification [161].This mineralization is associated with poor prognosis and is suppressed by the inhibition of TRPM7 or the chelation of intracellular calcium in human breast cancer cells.Increased Mg 2+ resulted in a protective effect, and this protection was independent of TRPM7 activity [162].On the other hand, low serum Mg 2+ activating TRMP7 has been suggested to increase intracellular Ca 2+ and Ca 2+ -related cell proliferation.The resulting high serum Ca 2+ /Mg 2+ ratio has been hypothesized to be a risk factor for postmenopausal breast cancer [163].
Recent studies showed that TRPM7 inhibitors interrupted the cell cycle, arresting the cells in the S phase, which suppresses the viability and migration of TRPM7 expressing breast cancer cells.Another investigation indicated that the TRMP7 antagonist carvacrol increased the proportion of cells in the G1/G0 phase and decreased the proportion of cells in the S and G2/M phases by regulating cyclin proteins.As a result, the suppression of cell growth and proliferation has been observed in human breast cancer cells [164][165][166].TRPM7 activity was shown to be associated with metastatic potential and migratory properties in human breast cancer tissue and cells.Furthermore, TRPM7 is part of the mechanosensory machinery that regulates cellular tension and steers adhesion dynamics thereby, promoting cell migration and metastasis formation [156].TRPM7 kinase domain and not Ca 2+ influx through the channel was suggested to be involved in breast cell migration via the phosphorylation of myosin IIA in metastatic estrogen receptor (ER) breast cancer.TRPM7 was implicated in the invasiveness and dissemination of tumor cells [157].In line with this observation, the blockade of TRPM7 kinase suppressed breast cancer cell migration and invasion in human breast cancer cell lines [167].
On the other hand, the activation of MAP kinase pathway via increased intracellular calcium levels in response to TRPM7 activation has also been proposed to cause an enhanced migration and invasion capacity of a human breast cancer cells in cul-ture [158].TRPM7 was proposed to be a partial regulator of EMT in breast cancer cells [168].Davis et al. have reported that the induction of EMT in breast cancer cells in response to TRPM7 activation depends on a cytosolic calcium signal.These mechanisms involve the regulation of EGF-induced STAT3 phosphorylation and vimentin expression.Another study also reported the partial involvement of TRPM7 in EGF-induced vimentin protein expression, but its calcium-dependent regulation was shown to occur via a TRPM7independent pathway [169].Wang et al. raised the possibility that the overexpression of TRPM7 in breast cancer cells resulted in an increased intracellular zinc concentration, which increased the level of MDMX (a negative regulator of the tumor suppressor p53), thereby promoting cell migration.The zinc-permeable channel function but not the kinase domain of TRPM7 was suggested to play an essential role in this observation [170].TRPM7 inhibitors have been reported to synergistically interact with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to enhance antiproliferative effects and apoptosis in triple-negative breast cancer cells.This effect was thought to be involved in TRPM7 channel activities (reduced Ca 2+ influx and the downregulation of cellular FLICE inhibitory protein) rather than TRPM7 kinase activities [171].
The expression of the transcription factor Sex-determining region Y-related highmobility group-BOX gene 4 (SOX4), a regulator of EMT in breast cancer cells, was promoted by TRPM7 via mechanical regulation by reducing myosin II-based cellular tension.This led to cytoskeletal relaxation and drove the mesenchymal features of breast tumor cells.TRPM7 has been also considered part of a mechanical signaling hub that controls cell plasticity [172] (Table 8).TRPM7 has been reported to be highly expressed in ovarian cancer and significantly associated with poor prognosis, tumor progression and decreased disease-free survival in a Chinese population [173].A subsequent study has revealed that TRPM7 mediates cell proliferation, migration and invasion in human ovarian cancer cell lines at least in part by influencing Akt, Src and p38 signaling pathways and the formation of cell adhesion complexes [174].TRPM7 expression correlates negatively with E-cadherin, but positively with N-cadherin, vimentin and Twist expression in human ovarian cancer cells.The upregulation of TRPM7 expression is associated with increased EMT.TRPM7 silencing decreased the EGF-induced migration, invasion and wound healing of cancer cells in vitro and metastasis formation in mice in vivo.The attenuation of calcium-related PI3K/Akt activation has been suggested as an underlying mechanism [175].Chen et al. have proposed that TRPM7 modulates glucose metabolic reprogramming involved in ovarian tumor cell proliferation.TRPM7 silencing suppressed the proliferation of ovarian cancer cells by shifting glycolysis to oxidative phosphorylation.This event was accompanied by decreased glucose uptake, increased AMP-activated protein kinase (AMPK) phosphorylation and decreased hypoxiainducible factor (HIF)-1α protein levels in ovarian cancer cells.TRPM7 levels were negatively correlated with IDH3B and UQCRC1, but correlated positively with hexokinase 2 (HK2) and pyruvate dehydrogenase kinase (PDK)1 expression in ovarian cancer tissue [176] (Table 9).

Uterine Tumors
Cervical cancer cell proliferation, invasion and migration were suppressed by miR-543 in vitro and tumor growth in vivo in part targeting TRPM7.PI3K/Akt and p38/MAPK pathways have been suggested to be involved in miR-543/TRPM7-regulated cervical cancer development [177].Furthermore, tumor suppressor miR-192-5p inhibited cervical cancer cell proliferation and invasion by targeting TRPM7 [178].Progesterone has been shown to reduce TRPM7 expression in human cervical cancer cells reducing cell proliferation and switching from necrosis to apoptosis [179].
A Turkish retrospective study revealed that TRPM7 may be a progression marker for endometrial hyperplasia (regardless of if it was categorized as "with atypia" or "without atypia") [180] (Table 9).

Prostate Cancer
The increased expression of TRPM7 in human prostate cancer cell lines has been repeatedly published.Moreover, a higher Ca 2+ /Mg 2+ ratio in prostate cancer patients resulted in increased Ca 2+ influx mediated by TRPM7, which promoted cell proliferation [181].TRPM7 was suggested to be involved in cholesterol-induced cell proliferation and the migration of human prostate cells.Cholesterol increased Ca 2+ entry via the TRPM7 channel, promoting the proliferation of prostate cells via the activation of the Akt and/or Erk pathway.Increased calpain activity and decreased E-cadherin expression was proposed to facilitate the migration of tumor cells [182].
The accumulation of HIF-1, playing a central role in tumor progression, is regulated by TRPM7 through a non-conventional RelB-dependent nuclear factor kappa B (NFκB) signaling pathway and the regulation of superoxide activity in osteosarcoma and prostate cancer cell lines [183].The anti-apoptotic effect of TRPM7 has been demonstrated in prostate cancer cells.TRPM7 inhibitors enhanced TRAIL-induced apoptosis in these cells [184].The TRPM7 antagonist carvacrol reduced prostate cancer cell proliferation, migration and invasion in prostate cancer cell lines.Reduced MMP-2 protein expression and F-actin dynamics as well as the suppression of PI3K/Akt and MAP kinase pathways have been shown to be involved in this effect [185].Chen et al. have also reported the suppressed migration and invasion of prostate cancer cells in response to the downregulation of TRPM7.The influence on the EMT (increased E-cadherin and Paxilin while decreased MMP-2 and MMP-9) was the underlying mechanism.TRPM7 seems to have a key role in metastasis [74].Transforming growth factor beta (TGFβ), known to promote the metastasis of prostate cancer inducing cell migration, and enhanced TRPM7 expression and function in prostate cancer cells.The consecutive Mg 2+ influx was essential for EMT-induced cell migration [186].A recent study revealed the mechanism of the involvement of TRPM7 in the growth and metastatic ability of prostate cancer cells under hypoxic conditions.Hypoxia increased TRPM7 expression and HIF-1α accumulation in androgen-independent prostate cancer cells.Annexin A1 has been suggested as a downstream mediator of EMT.TRPM7 knockdown promoted oxygen-independent RACK1-mediated HIF-1α degradation, resulting in the suppression of EMT, cell migration and invasion [187] (please see the summary of these data in Table 10).The expression of TRPM7 was reported in melanocytes and in cell lines derived from melanoma [188].Guo et al. have hypothesized that TRPM7 is a marker of deregulated metabolic activity in melanoma cells as well as a target for the restoration of protective and detoxifying properties in normal melanocytes [78].A recent study revealed that TRPM7 was involved in the proliferation of canine and human non-UV-induced melanomas.TRPM7 genes were suggested as candidate oncogenes for human mucosal melanoma [189] (Table 10).

Multiple Myeloma
TRPM7 has been shown to be upregulated in myeloma cells compared with normal plasma cells.The knockdown or inhibition of TRPM7 inhibited myeloma cell migration and dissemination [190,191].Myeloma cell motility and dissemination were suggested to be modulated by the Ca 2+ influx-O-GlcNAcylation regulatory axis linked to integrin α4 and β7.The inhibition of Ca 2+ influx channels such as TRPM7 repressed the aggressive tumor phenotype [191] (Table 10).

Conclusions
Here, we provided detailed descriptions of the role of TRPM7 in numerous tumor types of various organs and tissues, including expression profiles, tumor hallmarks and intracellular signaling pathways in an easy and quick-to-understand way with 10 tables.Data show that the TRPM7 chanzyme is expressed in most tumor cell types.In many cases, overexpression is detected, which is associated with an increase in tumorigenesis.However, the interpretation of these data requires caution from several points of view.In many studies, TRPM7 expression levels in tumor cells were not compared to thoser of normal cells.Furthermore, when its blockade might promise the inhibition of tumorigenesis, it is usually not clarified to what extent TRPM7 is a physiological part of normal functioning.Considering these uncertainties, how could we influence TRPM7 pathological functions selectively without affecting its physiological roles?This overview shows that in many cases, the signaling cascade involved in tumorigenesis was not clarified, including whether it is involved solely in aberrant/pathological or also in indispensable physiological functions.The TRPM7 chanzyme may be coupled to various signaling cascades in response to the influx of Ca 2+ , Mg 2+ or other divalent cations via the channel or phosphorylation by its kinase.A better understanding of the peculiarity of its double-channel/kinase function might provide a basis for the separation of physiological and pathophysiological functions of the chanzyme.However, only few tumor-related studies aimed to further elucidate this aspect.Revealing the regulation ofTRPM7 ion conductance under pathological conditions warrants further studies in the future.In addition, an understanding of changes in the trafficking and homo-and hetero-oligomerization of the chanzyme under pathological circumstances requires detailed examinations as well.
It is noteworthy that some experimental data are not in agreement with the general view that TRPM7 is involved in tumorigenesis, suggesting that it may even have a protective effect.A possible explanation for this observation is that different species and organ systems were investigated, different experimental models were used and the test conditions were different.However, the peculiarities of the functioning of the subtly regulated channel/kinase system might provide a more thorough and precise explanation of these data.Its clarification is of enormous scientific and practical interest.A better understanding of the underlying mechanisms of the TRPM7 dysfunctions resulting in malignancies may open the avenue for the prevention and more effective treatment of malignant disorders, thereby saving lives, alleviating suffering and saving healthcare resources.

Figure 1 .
Figure 1.Schematic representation of the protein structure of the TRPM7 chanzyme.

Figure 1 .
Figure 1.Schematic representation of the protein structure of the TRPM7 chanzyme.

Figure 2 .
Figure 2. Role of individual TRPM channels in the hallmarks of the various types of cancer.↑ indicates the increase and ↓ indicates the decrease in expression for each TRPM protein.For the references, please see [52-55,62,67-82].

Figure 2 .
Figure 2. Role of individual TRPM channels in the hallmarks of the various types of cancer.↑ indicates the increase and ↓ indicates the decrease in expression for each TRPM protein.For the references, please see [52-55,62,67-82].

Table 1 .
Role of TRPM7 chanzyme in the pathophysiology of glioblastoma.

Table 2 .
Role of the TRPM7 chanzyme in the pathophysiology of neuroblastoma.

Table 3 .
Role of the TRPM7 chanzyme in the pathophysiology of head and neck cancers.

Table 4 .
Role of the TRPM7 chanzyme in the pathophysiology of esophageal and gastric cancer.

Table 5 .
Role of the TRPM7 chanzyme in the pathophysiology of pancreatic and liver cancer.

Table 6 .
Role of the TRPM7 chanzyme in the pathophysiology of colorectal cancer.

Table 7 .
Role of the TRPM7 chanzyme in the pathophysiology of lung cancer and of the neoplasms of the urinary tract.

Table 8 .
Role of the TRPM7 chanzyme in the pathophysiology of breast cancer.

Table 9 .
Role of the TRPM7 chanzyme in the pathophysiology of ovarian and uterine cancer.

Table 10 .
Role of the TRPM7 chanzyme in the pathophysiology of prostate cancer, melanoma and multiple myeloma.